What is the CRH (corticotropin‑releasing hormone) stimulation test?

CRH Stimulation Test

What It Is

The CRH (corticotropin-releasing hormone) stimulation test is a diagnostic procedure that involves administering synthetic CRH intravenously and measuring the subsequent ACTH and cortisol responses to help differentiate between pituitary Cushing's disease and ectopic ACTH secretion in patients with ACTH-dependent Cushing's syndrome. 1

Primary Clinical Indications

The CRH test is specifically indicated in the following scenarios:

• Patients with confirmed ACTH-dependent Cushing's syndrome and a pituitary adenoma measuring 6-9 mm on MRI, where additional functional testing is needed before proceeding to surgery or bilateral inferior petrosal sinus sampling (BIPSS) 1

• Distinguishing true Cushing's syndrome from pseudo-Cushing's states in patients with mildly elevated screening tests, particularly those with psychiatric disorders, alcoholism, obesity, or PCOS 1

• When pituitary MRI is inconclusive or equivocal in patients with biochemically confirmed ACTH-dependent disease 1

How the Test Is Performed

Standard Protocol (Dex-CRH Test)

• Dexamethasone is administered first (typically 0.5 mg every 6 hours for 48 hours), followed by intravenous CRH administration 1

• Plasma dexamethasone, cortisol, and ACTH levels are measured at specific timepoints, with the 15-minute post-CRH measurement being most diagnostically accurate 1

• The test achieves 90% sensitivity and 95% specificity for diagnosing Cushing's disease when performed correctly 1

Dosing Considerations

• Either 100 μg human CRH or ovine CRH can be administered intravenously 2, 3

• Ovine CRH produces greater cortisol responses than human CRH (89.3% vs. 60.8% over baseline, P<0.05), resulting in superior diagnostic accuracy for cortisol response (71% vs. 49%) 3

• ACTH responses are comparable between human and ovine CRH, with equal diagnostic accuracy (86-87%) 3

Interpretation Criteria

For Cushing's Disease vs. Ectopic ACTH

• A cortisol rise >38 nmol/L at 15 minutes after CRH indicates pituitary Cushing's disease with >70% sensitivity 1

• A 50% increase in both ACTH and cortisol levels differentiates Cushing's disease from ectopic ACTH secretion with sensitivity and specificity greater than 80% 2

• Patients with ectopic ACTH secretion typically show no appreciable rise in ACTH or cortisol levels after CRH stimulation 3

For Pseudo-Cushing's States

• Patients with pseudo-Cushing's states show blunted ACTH responses to CRH, similar to normal individuals, helping distinguish them from true Cushing's disease 1, 4

• Peak ACTH and cortisol are lower in pseudo-Cushing's than in Cushing's disease, though percentage increases may be similar 2

For Adrenal vs. ACTH-Dependent Disease

• In patients with low (<10 pg/mL) or indeterminate (10-20 pg/mL) baseline ACTH levels, an absent or reduced peak ACTH response differentiates adrenal from ACTH-dependent forms 2

Important Technical Considerations

• Measuring plasma dexamethasone concentration at the time of CRH administration confirms adequate suppression and rules out false-positive results from abnormal dexamethasone metabolism 1

• For patients with cyclical Cushing's disease, the test should be performed immediately after confirming active hypercortisolism to ensure the patient is in an active disease phase 1

• All steroidogenesis inhibitors must be discontinued before the test, with appropriate washout periods based on each drug's half-life 1

Role in the Diagnostic Algorithm

The CRH test fits into the broader diagnostic pathway as follows:

1. After confirming hypercortisolism with screening tests (24-hour urinary free cortisol, late-night salivary cortisol, or dexamethasone suppression test) 5

2. After measuring morning ACTH to establish ACTH-dependent disease (ACTH >5 ng/L) 1

3. After obtaining pituitary MRI that shows either a 6-9 mm lesion or is inconclusive 1

4. Before proceeding to BIPSS, which remains the gold standard (96-100% sensitivity, near-100% specificity) when CRH testing is equivocal or unavailable 1

Limitations and Caveats

• No diagnostic test achieves 100% specificity, and discordant results occur in up to one-third of patients, requiring integration of clinical, biochemical, and imaging data 1

• The test has limited utility in diagnosing adrenal insufficiency, where its role is not well-established 2

• ACTH measurement can be performed by either RIA or IRMA with comparable diagnostic accuracy (87% vs. 84%, respectively) 3

• Baseline cortisol levels negatively correlate with ACTH and cortisol responses to CRH, suggesting persistence of negative feedback even in Cushing's disease 3